Liver failure occurs in a number of chronic and acute clinical conditions, including drug-induced hepatotoxicity, viral infections, vascular injury, autoimmune disease, and trauma. In addition, patients subject to genetic errors of metabolism may be at risk for developing liver failure. Symptoms of liver failure occurring as a result of these clinical conditions include, for example, acute hepatitis, chronic hepatitis, or cirrhosis.
Chronic liver disease is marked by the gradual destruction of liver tissue over time. Several liver diseases fall under this category, including cirrhosis and fibrosis, the latter of which is often the precursor of cirrhosis. Chronic hepatitis C virus infection and non-alcoholic steatohepatitis are two major causes of chronic liver disease. Once cirrhosis or fibrosis has occurred in the liver, it is generally considered irreversible. Conventional treatments currently focus on preventing any further progression of cirrhosis in the liver and mitigating the complications that can arise from cirrhosis. In more advanced stages of cirrhosis, the only known treatment is a liver transplant.
In acute liver disease, the liver is able to regenerate after being injured. If the disease progresses beyond the liver's capacity to regenerate new cells, the body's entire metabolism is severely affected. Loss of liver function may result in metabolic instability combined with disruption of essential bodily functions (i.e., energy supply, acid-base balance and thermoregulation). After large liver damage, liver tissue loses its regenerative and metabolic functions, and liver transplantation is a therapeutic strategy commonly used.
However, the clinical application of liver transplantation is limited by the availability of human hepatocytes, liver tissue and the number of liver cells that can be transplanted safely at one time.
A patient's ability to restore the pre-operative liver mass following major liver resection is well known. A variety of mediators are known to be hepatic mitogens, both in-vitro and in-vivo, but the precise mechanisms involved in liver regeneration remain to be defined (Michalopoulos, et al. Science, 1997, 276, 60-66). A significant problem with efforts to promote hepatic regeneration is that many therapeutic agents possess limited effectiveness in-vivo. The availability of pharmacological treatments to promote the regeneration of an adequate functional liver mass would therefore be a significant advance that could prevent many deaths from liver failure.
The ability to promote or increase hepatocyte proliferation in the clinical setting would have several important applications. It would allow previously unresectable hepatic malignancies to be resected by increasing the quantity of healthy hepatic tissue and preventing the patient's death from liver failure in the post-operative period due to inadequate remaining functional liver mass. Further, patients suffering from liver failure from toxic, metabolic, or viral causes may be spared death or a liver transplant if the native liver could be induced to regenerate at a rate that would restore adequate hepatic function prior to liver failure.
Despite ongoing research efforts, there remains a need for improved methods of promoting hepatic regeneration and repair. The development of therapeutic strategies that promote hepatocyte proliferation to treat liver damage caused by a range of hepatotoxic agents, diseases or pathological conditions is needed. The present invention addresses such needs.